Use of cannabinoids and terpenes for treatment of organophosphate and carbamate toxicity

ABSTRACT

Pharmaceutical compositions in which isolated cannabinoid receptor modulators are optionally combined with terpene blends in a pharmaceutically acceptable carrier. Methods for treating or preventing a disease disorder dysfunction or condition caused by exposure to an organophosphate or carbamate acetylcholinesterase inhibitor with the inventive compositions are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/004,004 filed on Jun. 08, 2018, which is a continuation of U.S.patent application Ser No.14/649,951 filed on Jun. 05, 2015, nowabandoned, which is a continuation of International Application Ser. No.PCT/US2013/076223 filed on Dec. 18, 2013, which claims priority to U.S.Provisional Application Serial No. 61/738,782, filed Dec. 18, 2012, nowexpired, the disclosures of which are incorporated herein by referencein their entireties.

FIELD OF THE INVENTION

The present invention discloses the novel uses of cannabinoid systemmodulators and terpenes in treatment of the symptoms and signs ofanticholinesterase toxicity associated with organophosphate (“OP”)and/or carbamate exposure. More particularly, the present inventionrelates to compositions containing cannabinoid receptor agonists andderivatives thereof, including partial agonists and modifiers ofcannabinoid metabolism and terpenes for prevention and treatment ofacute and chronic OP toxicity and acute and chronic carbamate toxicity.

BACKGROUND OF THE INVENTION

Organophosphates are compounds having the general chemical formula:

wherein R1 and R2 are alkyl-, alkoxy-, alkylthio- or amido groups and Xis an acyl residue or leaving group when the OP phosphorolatesacetylcholinesterase (AChE). The R groups are generally esters, amides,or thiol derivatives of phosphoric, phosphonic, or phosphinic acids. Inan OP, the O or (S) has a double bond with the central P. If the S ispresent the compound is a phosphorothioate but is still called an OPbecause of its mechanisms of action. Phosphorothioates must bebiotransformed to an oxon, with an O replacing the S, to become an OP.An example of such includes the biotransformation of parathion toparaoxon. Without the replacement of the S with an O, there is noinhibition of AChE. OP inhibition of AChE is initially reversible butmay become irreversible based on binding time.

Carbamates are carbamic acid derivatives and reversibly inhibit AChEhaving the general formula:

Carbamate insecticides include aldicarb (Temik), carbofuran (Furadan),carbartk (Sevin), methyl carbamate, ethienocarb, and others. Carbamateesters are also caused urethanes. OPs typically cause a more severe anddifficult to treat cholinergic crisis because OPs are capable ofirreversibly inhibiting AChE.

OP and carbamate compounds are typically used as insecticides,pesticides, petroleum additives, and petrochemicals. Deadly OPs andcarbamates have also been developed for use as chemical warfare nerveagents by conventional armies, military special forces, desperateregimes, and/or terrorists. Sarin, a highly potent OP, was used by SadamHussain's Republic of Iraq against Kurdish civilians in Halabja andother villages in March 1988 killing at least 3200 people and injuringmany more people. (These attacks also involved two other OPs, Vx andtabun and mustard gas). The 1995 Tokyo subway attacks by a “religious“cult” used the same OP injuring many civilians. The use of Sarin morethan once recently in the Syrian conflict lead to many casualtiesalarming the international community about the risks to the stability ofthe region.

Monocrotophos was the OP insecticide responsible for killing 23 schoolchildren in India who ate contaminated food, in a widely publicizedincident. At least 750,000 cases of OP poisoning occur every year.Mortality and morbidity is higher in poorer countries where OP andcarbamate pesticides, some of which are banned in developed countries,are inexpensive and accessible. They are estimated to cause around300,000 fatalities a year. See Balali-Mood et al, “Recent Advances inthe Treatment of Organophosphorous Poisonings”; Iran J. Med. Sci., 2012June; 37(2): 74-91. Pharmacologically, OPs behave as anticholinesteraseagents inhibiting the acetylcholinesterases (AChEs) enzymes and otheresterases resulting in increased cholinergic tone. In summary, OP andcarbamate pesticides cause hundreds of thousands of deaths each year andmany more injuries.

AChE is a serine protease in the carboxylesterase family of enzymes withEC number 3.1.1.7. Mammals have a single AChE gene; however, AChEdiversity in humans results from location, other molecular associationssuch as with membrane components, as well as from alternative mRNAsplicing and posttranslational associations or structural and catalyticsubunits. Inhibition of AChE prevents the breaking down of theneurotransmitter ACh thereby increasing both the level and duration ofaction of this neurotransmitter. ACh is a neurotransmitter thatcontributes to nerve conduction following its release in the centralnervous system (CNS) as well as autonomic ganglia at sympatheticpreganglionic synapses, at parasympathetic postganglionic synapses, andat neuromuscular junctions.

At the skeletal neuromuscular junction the ACh receptor is nicotinic. Inthe autonomic nervous system the ACh receptor is muscarinic. Bothmuscarinic and nicotinic ACh receptors are found in the central andperipheral nervous system. AChE catalyzes the hydrolysis of theacetylcholine into choline and acetic acid. Such a reaction is necessaryto allow a cholinergic neuron to return to its resting state afteractivation to restore normal muscle and neurological activities. AChEsare very efficient with each functional enzyme capable of hydrolyzing atleast 5000 ACh hydrolytic reactions per second. DFP ordiisopropylfluorophosphate is an OP developed in 1941. DFP bearsstructural similarity or homology with the nerve agent sarin. DFP hasactivity similar to sarin, although DFP is less potent. DFP is commonlyused as a research OP proxy for sarin. See generally Goodman & Gillman,The Pharmacological Basis of Therapeutics 10th edition, 2001, Chapter 7and Handbook of Toxicology of Chemical Warfare Agents, edited by RameshGupta, 2009, especially chapters 6, 7, 32, 33, 42, 43, 61, 63, and 64.

The effects of chronic and acute exposure to OP and carbamates have beenextensively documented in the literature. When OPs or carbamates areused as insecticides the prolonged exposure and inhalation of suchcompounds could lead to multiple ophthalmic and neuromuscular symptoms.OPs are also used as warfare nerve agents, (“nerve gas”) and acuteexposure to them by any route of exposure can be fatal. Carbamates mayalso be used in war or in terrorist attacks. Even if not fatal, exposuremay lead to temporary incapacitation as well as permanent cognitivedeficits, depression and other neuropsychiatric disorders. Currenttreatment after acute injury does not seem to prevent the emergence of“Organophosphate induced delayed neuropathy,” an axonopathy. In anyevent, OP and carbamate casualties require medical intervention anddecontamination.

Nerve agents, also called gasses regardless of physical state, areclassified by the US military and into two types of agents, the G- andthe V-class agents. G-agents such as tabun (G A) and sarin (GB) wereoriginally synthesized by a German group during the 1930s and except fortabun (GA; ethyl N,N-dimethylphophoramidocyanidate) include fluorinatedcompounds of organophosphate, such as sarin (GB;2-fluoromethyl-phophoryloxypropane), soman (GD;3-fluoro-methyl-phosphoryloxy-2, 2-dimethyl-butane), and cyclosarin (GF;fluoro-methyl-phophoryloxycyclohexane). G agents are volatile liquids atroom temperature with a slightly higher density than water. Theirprimary route of entry is via the respiratory tract and mucous membranessuch as the eye. Because of their high volatility G agents areconsidered non persistent nerve agents. Toxic exposures are most likelyto be via eye, mouth, nose, and especially involve the respiratory tractunless filtered and/or neutralized by an improvised or purposely builtgas mask. G agents in liquid form may penetrate skin and as well asvolatilize presenting significant respiratory hazards. The respiratorytract tissues, primarily the air sacs or alveoli, provide a largesurface area, about 100 square meters. The skin surface area in about1.73 square meters. Loss of consciousness is expected in less than oneminute with death expected in less than 15 minutes following 2 deepbreaths of highly concentrated G class vapors. Since G agents and someOP pesticides are colorless, tasteless, and virtually odorless, they mayalso be accidently ingested into the GI tract or ingested via deliberatecontamination of food and drinking liquids.

V-agents were initially synthesized after World War II by scientistsfrom the United Kingdom. The V agents are sulfur containingorganophosphate compounds including VE (S-2-diethylamino ethylO-ethylethylphophonothioate), VG (2diethoxyphosphorylsulfanyl-N,N-diethylethanamine), VM(2-ethoxy-methylphosphoryl sulfanyl-N,N-diethylethanamine), VR or RVX(Russian VX; N,N-diethy-2-methyl-2-methylpropoxy phosphorylsulfanylethanamine) and VX (S-2 diisopropylaminoO-ethylmethylphosphonothioate). The V-agents, oily liquids at roomtemperature that very slowly release gas due to their low volatilities,are both more toxic, as well as longer persisting in the environmentthan the G-agents. Their primary, but not the sole route of entry, isvia skin contact. A single drop of VX the size of this dot (.) unlessrapidly decontaminated or removed, may be fatal within 30 minutes ifplaced on intact thin moist skin, faster if on a wound, and within 120minutes if on dry thick skin. The human LD 50 for VX is 10 mg.

Toxicity associated with OP compounds mainly results from excessivecholinergic stimulation through inhibition of ACKE. The resultinghypercholinergic tone crisis may also cause other neuronalhyperexcitation, e.g., glutamate release and depletion of high energyphosphates leading to cellular damage and physiological exhaustion.Nerve agents react rapidly with a serine hydroxyl, group in the activesite of AChE to form a phosphate or phosphonate ester. PhosphorylatedAChE is not able to functionally hydrolyze ACh. Functional AChregenerates very slowly. ,Thus, the enzyme will remain inhibited untilnew enzyme is generated, or until an enzyme re-activator toxime) isused, as long as receptor aging or irreversible binding from molecularrearrangements of the AChE from the effect of the OP has, yet notoccurred.

As depicted in the schematic above, AChE represented by the Enzyme,contains serine in the active (esteratic) site. Following the binding ofDFP to this site the AChE is inactivated. This inactivation of AChE maybe hydrolyzed slowly and spontaneously or rapidly reversed or restoredwith an oxime (and perhaps other chemicals). However, the binding orinhibition can eventually become petmanent (irreversible or aged).

The symptoms of OP and carbamate toxicity are receptor and body sitespecific. Nerve aaents antagonize muscarinic receptors to cause miosis,ocular ciliary or pupillary constrictor muscle spasm and eye pain,glandular laypersecretion (salivary, bronchial, lacrimal/tear glands),bronchoconstriction, vomiting, diarrhea, urinary and fecal incontinence,and bradycardia.

Nerve agents act on nicotinic receptors to cause sweating, hypertension,tachycardia, and on skeletal muscle, they cause initial fasiculations,twitching, tremors, spreading areas of spasm, and defasciculation fromexhaustion followed by weakness and flaccid paralysis.

Nerve agents also antagonize cholinergic receptors to produceirritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures,coma, respiratory depression, and paralysis. Nerve agents independentlycause cardiac tachycardia and hypertension via stimulation of theadrenal medulla. Exposure to low concentrations of nerve agent vaporfurther produce immediate ocular symptoms, including rhinorrhea (fromnasolacrimal duct drainage), and in some patients, even dyspnea. Theseocular effects are secondary to the localized absorption of vapor acrossthe outermost layers of the eye, causing lacrimal gland stimulation(tearing), pupillary sphincter contraction (miosis), and ciliary bodyspasm (ocular pain).

As the exposure increases, dyspnea and gastrointestinal symptoms ensue.Intoxication signs and symptoms and treatment of patients exhibiting OPor carbamate toxicity is similar. Retrospective data review seriesinvolving OP and carbamate toxicity are frequently combined. See forexample the 46 patient 5-year review from Jordan, a country where OP andcarbamate agricultural insecticides are widely used. These chemicals arealso used as agents in suicides and to injure enemies. See AM Saadeh etal, “Cardiac manifestations of acute carbamate and organophosphatepoisoning” Heart, 1997; 77:461-464.

It is well documented that exposure to high concentrations of nerveagent vapor causes immediate loss of consciousness, followed shortly byconvulsions, flaccid paralysis, and respiratory failure. Thesegeneralized effects are caused by the rapid absorption of nerve agentvapor across the respiratory tract, producing maximal inhibition of AChEwithin seconds to minutes of exposure. Nerve agent vapor exposure,unless aggressively treated and to include decontamination to preventreexposure to patient and also endanger rescuer, is expected to havesignificant effects by the time victims present to the emergency caresystem. Decontaminants include soap and water as well as the moreeffective expedient dilute chlorine bleach solutions for skin, dilutebaking soda (sodium bicarbonate) solutions for eyes, nostrils, hair,ears, mouth, and other delicate tissues and genitourinary mucousmembranes, or RSDL. RSDL is Reactive Skin Decontamination Lotion, aspecialty pharmaceutical topical product issued to combat soldiers andsome first responders. RSDL achieves a much more rapid and effectivedecontamination than any of the expedients.

The effect of dermal exposure from liquid nerve agent depends on theanatomic site exposed, ambient temperature, and dose of nerve agent.Percutaneous absorption of nerve agent typically results in localizedsweating caused by direct nicotinic effect on the skin, followed bymuscular fasciculations and weakness as the agent penetrates deeper anda nicotinic effect is exerted on underlying muscle. Following moderatedermal exposures, vomiting and/or diarrhea occur. Vomiting and/ordiarrhea soon after exposure are ominous signs. With further absorption,full-blown systemic or remote effects occur. Nerve agents cause deathvia respiratory failure, which in turn is caused by increased airwayresistance (e.g., bronchospasm), excessive bronchopulmonary secretions,respiratory muscle paralysis, and most importantly, loss of centralrespiratory drive.

Other studies have shown that nerve gases such as sarin produced delayedand long-term effects on cardiac function such as reduced ejectionfraction. Sarin caused left ventricular dilation two months after anasymptomatic dose. This is a marker for dilated cardiomyopathy. Levelsof atrial and brain natriuretic peptides in the heart were increased,indicating cardiac remodeling possibly due to volume overload. It hasalso been reported that prolonged exposure to OP leads to cognitiveimpairment of central information processing leading eventually to IQloss. See Davis et al, Advances in Psychiatric Treatment, 2000; 6:187-192.

The treatment modalities generally depend on severity of intoxication.In addition to decontamination, there are several treatments forintoxicated patients. More specifically, such treatments includeadministration of intravenous or intramuscular atropine, at least 2 mgat a time for adults, to counteract muscarinic over-stimulation, and anintravenous or intramuscular oxime, typically pralidoxime or 2-PAM, toreactivate acetyl cholinesterase. For example, the US military uses asfront line therapy autoinjectors for IM administration combining 2.1 mgof atropine with 600 mg of 2-PAM. If fasciculation or seizures arepresent, the US military, prior to arrival of a medic, uses as a GABA Aanti-seizure agent IM diazepam 10 mg in an autoinjector. Soldiers aregiven kits containing 3 autoinjectors of the combinationatropine/pralidoxime and 3 autoinjectors containing diazepam 10 mg.There is no ceiling on the dose of atropine: additional injections aretitrated vs adverse symptoms other than miosis every few minutes asneeded. In other countries, armed forces and/or emergency protocols usea different oxime, e.g., obidoxime or HI6, a different antimuscarinic(anticholinergic), e.g., scopolamine and/or other belladonna alkaloidsin place of atropine, and a different anti-seizure agent, e.g.,avizafone or midazolam or barbiturates. For some patients the dose ofatropine required may exceed 100 mg! In the absence of OP intoxicationan atropine dose of 2 mg will cause severe poisoning and a dose of 100mg will be fatal. For this reason, Israel stopped including atropinewith its gas mask kits for civilians after severe adverse reactions toatropine happened in civilians who injected atropine in response tosirens warning of incoming SCUD missiles during the first Gulf War in1991.

Supportive and intensive care therapy includes the use of oxygen, IVfluids, glucose, and electrolytes (salts) and bicarbonate, to replacethe fluids and salts and bicarbonate lost from vomiting, diarrhea,profuse sweating (diaphoresis) and respiratory secretions. In addition,titrated IM and IV diazepam to control convulsions, atropine/oxime,mechanical respiration, and intensive cardiorespiratory and neurologicalsign monitoring with aggressive treatment of cardiac rhythm disordersand pulmonary edema. Experimental cholinesterase infusions are alsobeing researched as are catalytic scavengers that would split an OPmolecule to render it inactive, such as from infusions of FFP or FreshFrozen Plasma, or from stoichiometric scavengers to bind an OP andantibodies against OPs. Recent investigations have revealed thatintravenous infusion of sodium bicarbonate to produce mild to moderatealkalinization is effective. Gacyclidine, an antiglutamatergic compound,was also proved to be beneficial in conjunction with atropine,pralidoxime, and diazepam in nerve agent poisoning. Intravenousmagnesium sulfate was reported to decrease hospitalization duration andimproved outcomes in patients with organophosphorous poisoning frompesticides. Ketamine may also be useful if given early. See Balali-Moodet al, Iran J Med Sci. 2012 June; 37(2): 74-91.

At present, pyrostigimine bromide 30 mg tablets (PB) every 8 hours seemsto be the most common prophylactic. PB is approved for military medicaluse by the US FDA at this dose and frequency for this indication forsoman. G-agent soman ages the AChE in under 2 minutes. Soman is probablythe most rapidly aging OP (based on non-classified or public domaindata). Pre-exposure treatment with PB sequesters some AChE from OPbinding and aging. Any subsequent post OP or post carbamate intoxicationis more rapidly and more effectively treated with atropine/oximetherapy. Like all medications PB has adverse effects. Adverse reactionsto PB include salivation, lacrimation, urination, defecation symptomsand miosis. Prophylactic use of PB has also been linked to the Gulf WarSyndrome. Regimens used by trained soldiers acting under militarymedical orders in other countries include prophylactic tablets withphysostigmine rather than pyridostigmine with or withoutTrihexyphenidyl, benactyzine, and/or a transdermal patch containingHI-6.

Access to effective prophylaxis and treatment has important implicationsfor military or civilian populations since low-dose, non-symptomaticexposure to OPs or carbamates may result in long-lasting effects. SeeFusek et al, Curr. Med. Chem. 2009; 16(23):2977-86 and Chapter 63,Prophylactic and Therapeutic Measures in Nerve Agent Poisoning inHandbook of Toxicology of Chemical Warfare Agents, edited by RameshGupta, 2009, and US Prescribing Information for Physostigmine bromide 30mg for military medical use.

However, since pyridostigmine barely crosses the blood-brain barrier itprovides no protection against nerve agent-induced central injury.Pyridostigmine, as written in the FDA approved prescribing information,is ineffective when administered without post-exposure treatment ofatropine/2 PAM or similar drugs. Also many of the prophylactic andtreatment regimens cause cognitive impairment or excessive dryness(e.g., atropine and other antimuscarinics), certainly not desirable incombat situations or hot environments where perspiration also serves asa temperature regulator. Excessive dryness increases the chances of heatexhaustion related disorders including heat stroke.

Therefore, other directions for different types of prophylactic andnon-injection, less expensive, and self-administered treatments (orthose not requiring an intensive care unit for potentially therapy)should be explored. Atropine overdose or misuse risks heat stroke andtemporary psychosis. A common mnemonic used to describe the physiologicmanifestations of atropine overdose is: “hot as a hare, blind as a bat(from very dilated pupils and cycloplegia), dry as a bone, red as abeet, and mad as a hatter”. These associations reflect the specificchanges of warm, dry skin from decreased sweating, blurry vision withhypersensitivity to light, decreased sweating/lacrimation, vasodilation,and central nervous system effects on muscarinic receptors, type 4 andtype 5. This set of symptoms is known as anticholinergic toxidrome.

Recently there have been discussions on combination prophylactictherapies including such compounds as carbamates (reversible AChEinhibitors) and central anticholinergics or NMDA receptor antagonists,benzodiazepines or partial agonists for benzodiazepine receptor, andother central AChE inhibitors. The transdermal route is an alternativeway for delivering the prophylactic agent and has also been discussed inthe art. Regardless, there is still a need for additional prophylacticor adjunct to existing prophylactic regimens to mitigate drug relatedadverse events or direct treatments to alleviate undesired symptomsassociated with the OP and carbamate toxicities. There is a needparticularly for nontoxic treatment modalities, with favorabletherapeutic indices compared with PB, atropine and such respiratorydepression-inducing anticonvulsants as midazolam, diazepam, andbarbiturates. There is a need for anti OP and carbamate therapy that maybe easily self-administered or easily administered by first respondermedics and paramedics in mass casualty situations or even by lightlyinjured casualties to each other and to more seriously injuredcasualties. In the event of mixed nerve agent/conventional warfarecasualties, there is also a need for antidotes to the nerve agents thatwon't have significant drug/drug interactions with medications used totreat surgical wounds including general anesthesia agents. The presentinvention addresses such shortcomings.

SUMMARY OF THE INVENTION

The present invention discloses the role of cannabinoids in mitigatingOP toxicity via manipulation of the endocannabinoid (EC) system andother physiological systems.

In one embodiment, the present invention discloses a pharmaceuticalcomposition comprising an isolated cannabinoid receptor modulator, andoptionally containing a blend of terpenes in a pharmaceuticallyacceptable carrier.

In another embodiment, the present invention discloses a pharmaceuticalcomposition further comprising a blend of two or more terpenes selectedfrom the group consisting of limonene, pinene, myrcene, linalool, betacaryophylene, terpineol, and terpinolene.

In another embodiment of the invention, the terpene blend comprises twoor more terpenes selected from the group consisting of limonene, pinene,myrcene, linalool, and beta caryophylene.

In another embodiment of the invention, the weight ratio of saidterpenes is in range of about 1-10: about 1-10: about 1-6: about 1-6:0.25-3, respectively. In another embodiment of the invention, the weightratio of said terpenes is about 4:4:3:3:1 respectively.

In another embodiment of the invention, the weight ratio of saidterpenes is about 4:7:3:3:1 respectively.

Another embodiment of the present invention discloses a pharmaceuticalcomposition, wherein said cannabinoid receptor modulator agonist is a CBreceptor agonist or a modifier selected from the group consisting ofphytocannabinoids, tetrahydrocannabinol (THC), (−)-trans-delta-9-THC,dronabinol, (±)-trans-3-(1,1-dimethylheptyl)-6,6a,7, 8,10, 10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (nabilone),anandamide, 2-arachidonoyl-glycerol (2-AG),N-acyl-phosphatidylethanolamine-phospholipase D, diacyl glycerol lipase(DAGL), cannabidiol (CBD), abnormal cannabidiol (abn-CBD), nabiximols,EPIDIOLEX®, rimonab ant, (−)-1,1-dimethylheptyl analogs of11-hydroxy-8-tetrahydrocannabinol (HU 210), HU 211, HU 308, ajulemicacid, AM-411, L-759,633, AM-855, VCHSR, nonabine, JWH 133, JWH-171,BML-190, A-41988, O-806, O-2694, O-2545, JZL184, JWH-359, CB-13,GW-405,833, JTE-907, URB754, inhibitors of FAAH or fatty acid amidehydrolasel-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole(AM-1241), WIN 55,212-2, other natural or endogenous endocannabinoidderivatives, and combinations thereof.

The pharmaceutical composition of the present invention is in oral,nasal, topical, ophthalmic, buccal, sublingual, rectal,vaporization-ready, nebulization-ready, nanoparticle formulations,liposomal formulations, vaginal and/or IV or other parenteral form.

The pharmaceutical composition of the present invention furthercomprises one or more non-cannabinoid active ingredients selected fromthe group consisting of a terpene, a benzodiazepine, a belladonnaalkaloid, an anticholinesterase, an oxime, and combinations thereof.

In an embodiment of the invention, belladonna alkaloid is atropine andanticholinesterase is pyridostigamine.

Another embodiment of the invention is directed to a method of treatingor preventing a disease, disorder, dysfunction, or syndrome caused byexposure to an organophosphate (OP) or carbamate acetylcholinesteraseinhibitor, said method comprising administering to a subject exposed toor at risk of exposure to said OP or carbamate a pharmaceuticalcomposition of the present invention in an amount effective to modulatethe cannabinoid receptors of said subject.

In an embodiment of the invention, the pharmaceutical composition is fortreating disease, disorder, dysfunction, or syndrome selected from thegroup consisting of muscle disorder, ophthalmic dysfunction, metabolicdisorders, cardiac, rhythm and contractility dysfunctions, socialrelated disorders, mood disorders, seizures, learning disorders,cognition disorders, memory disorders, respiratory disorders, locomotoractivity disorders, movement disorders, immune disorders, inflammation,cell growth, pain or neurodegenerative related syndromes, drug abuse,alcohol abuse, bipolar disorder, cognitive impairment, post-traumaticstress disorder (PTSD), Gulf War like syndrome, and premature seniledementia.

In one embodiment of the invention, the muscle disorder is selected fromthe group consisting of dyskinesia, akinesia, tremor, bradykinesia, andskeletal muscle rigidity and spasticity.

In one embodiment of the invention, the ophthalmic disorder is selectedfrom the group consisting of miosis, ciliary muscle spasm, ophthalmicpain, headache, and lacrimation disorder.

In another embodiment of the invention, the OP is a G or V class nerveagent.

In another embodiment of the invention, the cannabinoid receptormodulator is selected from the group consisting of phytocannabinoids,tetrahydrocannabinol (THC), (−)-trans-delta-9-THC, dronabinol,(±)-trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one(nabilone), anandamide, 2-arachidonoyl-glycerol (2-AG),N-acyl-phosphatidylethanolamine-phospholipase D, diacyl glycerol lipase(DAGL), cannabidiol (CBD), abnormal cannabidiol (abn-CBD), nabiximols,EPIDIOLEX®, rimonabant, (−)-1,1 dimethylheptyl analogs of11-hydroxy-8-tetrahydrocannabinol (HU 210), HU 211, HU 308, ajulemicacid, AM-411, L-759,633, AM-855, VCHSR, nonabine, JWH 133, JWH-171,BML-190, A-41988, O -806, 0-2694 and O-2545, JZL184, JWH-359, CB-13,GW-405,833, JTE-907, URB754, inhibitors of FAAH or fatty acid amidehydrolasel-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole(AM-1241), WIN 55,212-2, other natural or endogenous endocannabinoidderivatives, and combinations thereof.

Another embodiment of the invention provides for administering anon-cannabinoid receptor modulator selected from the group consisting ofopioids, gabapentins, pregabalins, benzodiazepines, atropines, oximes,antioxidants, alkalizing agents, terpenes, and NSAIDs.

Another embodiment of the invention provides for administering thecomposition in oral, nasal, topical, ophthalmic, buccal, sublingual,rectal, vaporization-ready, nebulization-ready, nanoparticleformulations, liposomal formulations, vaginal and/or IV or otherparenteral form.

Another embodiment of the invention provides for administering thecomposition prior to exposure to said organophosphate or carbamate andsaid composition comprises at least one terpene selected from the groupconsisting of limonene, mycrene, pinene, linalool, beta caryophyllene,and a cannabinoid selected from the group consisting of THC, CBD, and amixture of THC and CBD.

Another embodiment of the invention provides for the step of exposingsaid subject to an OP or carbamate acetylcholinesterase inhibitor as aprophylactic treatment.

Another embodiment of the invention provides for administering to asubject atropine and an oxime in an amount effective to prevent adverseeffects from said prophylactic exposure to OP or carbamate.

Another embodiment of the invention provides for co-administeringpyridostigmine bromide to a subject.

Another embodiment of the invention provides for administering to saidsubject after exposure to an OP or a carbamate acetylcholinesteraseinhibitor and said composition comprises a blend of CBD and THC in aweight ratio of between about 3 and 400 mg to about 0.0001 and 10 mg,respectively.

Another embodiment of the invention provides for administering a blendof two or more terpenes.

In another embodiment of the invention the terpine blend comprises twoor more terpenes selected from the group consisting of limonene, pinene,myrcene, linalool, beta caryophylene, terpineol, and terpinolene.

Another embodiment of the invention provides for a method of treating orpreventing a disease, disorder, dysfunction, or syndrome caused byexposure to an organophosphate or carbamate acetylcholinesteraseinhibitor, said method comprising administering to a subject exposed toor at risk of exposure to said OP or carbamate a composition comprisingat least two terpenes selected from the group consisting of limonene,myrcene, linalool, beta caryophylene, terpineol, terpinolene, andpinene, in an amount effective to treat or prevent said disease,disorder, dysfunction, or syndrome.

Another embodiment provides for a terpene mixture comprises alphapinene.

Another embodiment provides a blend which comprises beta-caryophylene,limonene, myrcene, and linalool.

Another embodiment provides a compound having the following structure:

wherein L is selected from the group consisting of

Z═O, S or NR7, R7=H, alkyl, aryl, —OH, —O, or a lower alkoxy; A is aryl,heteroaryl, fused pyran, or a fused tetrahydropyran; B is C(═O)—O—R6; R6is an alkaloid azabicyclo ring substituent; C is H, F, lower alkoxy, CN,S(O)nCH3, where n=O-2, and Z═O.

Another embodiment provides a compound selected from the groupconsisting of:

In another embodiment such compounds may be administered to a subject inneed in effective doses corresponding to the therapeutic doses of THC,CBD and/or atropine. The composition of the present invention may beused to treat symptoms associated with OP or carbamate exposure. Suchsymptoms include ocular symptoms, skeletal motor symptoms, respiratoryand CNS associated symptoms. In another embodiment, the ocular symptomsto be treated include lacrimal gland stimulation (tearing), painfulpupillary sphincter contraction (miosis), and ciliary body spasm (ocularpain). In another embodiment, the respiratory symptoms being treatedinclude dyspnea, bronchospasm, coughing, rhinorrhea, bronchorhea,respiratory distress, sensation of shortness of breath, respiratoryfailure, pulmonary edema, and air hunger. The gastrointestinal symptomsthat ensue after exposure usually include hyper salivation, vomiting,diarrhea, and stomach cramps.

In another embodiment, the symptoms being treated include motor symptomssuch as fasiculations, dyskinesia, akinesia, tremor, bradykinesia,skeletal muscle rigidity, and spasticity. In yet another embodiment, theCNS symptoms being treated include cognitive brain damage, neuropathyincluding axonopathy, anxiety, memory impairment, PTSD, and depression.

In at least one aspect of the present invention, the composition of thepresent claims may be administered either directly or indirectly to thesite of interest by way of eye drop, eye ointment, oral spray, rectalsuppository, intravenously, intramuscularly, subcutaneously,intradermally, orally in the form of capsules or tablets or dilutedoils, topical rubs on the skin or mucous membrane, or buccally.Alternatively, the formulation may be applied directly to the site ofinterest such as via nasal application devices to sphenopalatineganglion and cribriform plate, which is the pathway to the olfactorycranial nerve and brain, as well as the cerebrospinal fluid or by way ofinhalation of vapors for rapid absorption. In the alternative, theformulation may also be introduced as a vapor into a gas mask, bag/valvemask used in manual resuscitation or assisted breathing, nasalcannulation, CPAP, or Continuous Positive Airway Pressure or variants ofCPAP such as BiPAP, or via intubation with or without generalanesthesia. Other objects, features, benefits and advantages of thepresent invention will be apparent from this summary and the followingdescriptions of certain embodiments, and will be readily apparent tothose skilled in the art having knowledge of various chemotherapeuticcompounds, methods and/or modes of operation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A depicts the composition of the inventive terpene blendsdescribed herein.

FIG. 1 B depicts the composition of the inventive terpene blendsdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as are commonly understood by one of skill in theart to which this invention belongs and shall be understood to have themeanings described below. All publications and patents referred toherein are incorporated by reference in their entirety.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including racemic and other mixturesthereof. Unless otherwise specified, a reference to a particularcompound also includes ionic, salt, solvate (e.g., hydrate), protectedforms, prodrugs, and other stereoisomers thereof, for example, asdiscussed herein.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.

The term “lower alkoxy” is defined as C₁ to C₃ alkoxy.

The term “benzodiazepine” as used herein pertains to all different shortand long acting benzodiazepines, including but not limited to prodrugs,as well as estazolam, flurazepam, temazepam, triazolam, alprazolam,chlordiazepoxide, clorazepate, diazepam, halazepam, lorazepam,midazolam, oxazepam, prazepam, quazepam, and clonazepam. Benzodiazepineantagonists are thus such compounds that antagonize the benzodiazepineactivities, especially respiratory depression secondary tobenzodiazepine toxicity.

The term “cannabinoid” as used herein pertains to all differentcannabinoids that have been isolated from the Cannabis sativa plant orsynthetically created to have activity involving the endocannabinoidsystem. The term cannabinoid includes, but are not limited to, allclasses of cannabinoids from Cannabis derived from cannabigerol-typecompounds, including (9THC), cannabidiol (CBD), cannabinol (CBN), anddodeca-E,4E,8Z,10E/Z-tetraenoic-acid-isobutylamides, cannabigerol (CBG),cannabichromene, cannabicyclol(CBL), cannabivarin (CBV),tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin(CBCV), cannabigerovarin (CBGV), and cannabigerol monomethylether(CBGM).

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “organophosphate” as used herein, pertains to compounds thatare generally esters, amides, or thiol derivatives of phosphoric,phosphonic, or phosphinic acids. Aside from certain limited medicaluses, these compounds are typically used as insecticides, pesticides,petroleum additives, and even warfare nerve agents. Organophosphatesinclude substances such as echothiophate, diisopropyl fluorophosphate(DFP), tabun, GA, GB (sarin), GD, GF, VX, VE, VG, VM, diazinon,malathion, and parathion.

The term “terpenes” or “terpenoids” as used herein refers to a class ofhydrocarbon occurring volatile molecules that provide a unique smell.Terpenes are derived from units of isoprene, which has the molecularformula C₅E1₈. The basic molecular formulae of terpenes are multiples ofthat, (C₅H₈). where n is the number of linked isoprene units. Theyinclude but are not limited to limonene, beta-caryophyllene, myrcene,linalool, pinene, terpineol, and terpinolene, and any isomeric formsthereof.

The term “treatment” or “therapy” as used herein in the context oftreating a condition, pertains generally to treatment and therapy of ahuman subject, in which some desired therapeutic effect is achieved. Forexample, therapy can include the inhibition of the progress of thecondition, reduction in the rate of progress, a halt in the rate ofprogress, amelioration of the condition, absolute or partial preventionof a delayed complication, and cure of the condition. Treatment alsoincludes prophylactic measure as well as adjunct treatments to astandard treatment regimen established in the art.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of an active compound, or a material, composition or dosageform comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonablebenefit/risk ratio.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in the form of a prodrug. The term “prodrug” as usedherein, pertains to a compound which, when metabolized, yields thedesired active compound or in itself is the active compound. Typically,the prodrug is inactive, or less active than the active compound, butmay provide advantageous handling, administration, or metabolicproperties. For example, some prodrugs are ethers or esters of theactive compound; during metabolism the ether group is cleaved to yieldthe active drug. Also, some prodrugs are activated enzymatically toyield the active compound, or a compound which, upon further chemicalreaction, yields the active compound. Thus, in the methods of treatmentof the present invention disclosed herein, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Metabolites of these compoundsinclude active species produced upon introduction of compounds of thisinvention into the mammalian subject.

Any of the compounds of the present invention may be contemplated foradministration to the human subject in the form of a drug, prodrug oreven active metabolite.

The cannabinoid and the THC-CBD combinations have been known in the artfor treating or preventing a number of diseases or disorders. Forexample, U.S. Pat. No. 6,630,507 discloses cannabinoids for use asanti-oxidants and neuro-protectants; U.S. Pat. No. 7,105,685 disclosesCannabinoids for the treatment of diseases associated with immunedysfunction, particularly HIV disease and neoplastic disorders; U.S.Pat. No. 7,109,245 discloses Cannabinoids useful as vasoconstrictors; USPatent Publication US20110257256 discloses THC-CBD composition for usein treating or preventing Cognitive Impairment and Dementia; PCTPublication WO/2009/147439 discloses use of a combination of THC and CBDin the manufacture of a medicament for use in the treatment of cancer,in particular the glioma tumor (a brain cancer); PCT PublicationWO/2007/148094 discloses use of THC-CBD composition for the treatment ofneuropathic pain; and US Patent Publication US20100286098 discloses amethod of treating tissue injury in a patient with colitis administeringthe THC-CBD combination.

Currently, US Drug Enforcement Administration (DEA) lists cannabis as aSchedule 1 compound which means Cannabis and similarly scheduledcannabinoids have not been shown to have safety and/or accepted medicaluse. However, different combinations of cannabinoids are still underinvestigation.

The psychoactive constituent in cannabis, 9THC, was isolated in theperiod 1963-64 by Prof. Raphael Mechoulam, but the cannabinoidreceptors, the CB1 and the CB2, and the preliminary endogenouscannabinoids, e.g., anandamide and 2-arachidonoyl glycerol, wereidentified only 20 to 25 years later. The cannabinoid system affectsboth central nervous system (CNS) and peripheral processes. In at leastone aspect of the invention, methods of manufacturing a pharmaceuticalcomposition containing a cannabinoid is contemplated, including thesteps of purifying and/or isolating the cannabinoid receptor agonist andmixing said agonist with a pharmaceutically acceptable carrier.

In one aspect of the present invention, methods of ameliorating ortreating a cannabinoid receptor mediated disease, disorder or syndromein a human subject are disclosed by such steps as administering to thesubject an effective amount of a composition containing cannabinoidreceptor modifiers and/or terpenes such as d-limonene, pinene, myrcene,linalool, beta caryophylene, or a combination thereof.

More particularly, the present invention relates to a method of treatingOP or carbamate related toxicity in human patients. In this aspect ofthe invention, methods are provided for modulating the CB system toreduce functional signs or toxicity following exposure to OP orcarbamate. In such a method, patients receive a therapeuticallyeffective amount of EC system modulator for sufficient time to reducethe time of acetylcholine binding to its respective receptors therebylimiting cholinergic signs of toxicity associated with prolonged OPexposure.

In at least one embodiment, the mediated disease, disorder, dysfunctionor syndrome being treated is secondary to organophosphate exposure andincludes appetite disorder (such as loss of appetite), muscle disorder,ophthalmic dysfunction, metabolic disorders, cardiac, rhythm andcontractility dysfunctions, social related disorders, mood disorders,seizures, substance abuse, learning disorders, cognition disorders,memory disorders, respiratory disorders, locomotor activity disorders,movement disorders, immune disorders, inflammation, cell growth, pain orneurodegenerative related syndromes, substance abuse including alcoholabuse, bipolar disorder, cognitive impairment, post-traumatic stressdisorder (PSTD), Gulf War syndrome type disorders, and premature seniledementia. In a preferred embodiment, the instantly described methodologyis used as an adjunctive treatment to the standard medical regimentypically used for OP toxicity.

In another embodiment, the muscle disorders are dyskinesia, akinesia,tremor, bradykinesia, and skeletal muscle rigidity and spasticity. Inanother embodiment the ophthalmic disorders are miosis, ciliary musclespasm, ophthalmic pain, headache and lacrimation disorder.

In yet another embodiment, the present invention is directed to methodsof antagonizing G and V class nerve agent organophosphate toxicity viaadministering to a subject in need thereof a cannabinoid receptoragonist, its free base, or in pharmaceutically acceptable salt form anda pharmaceutically acceptable carrier. Such toxicities include thosethat lead to permanently cognitive impairment, such as attention deficitdisorder, executive function disorder, loss of coordination particularlywhen operating hazardous machinery, learning disability, safe driving,and delayed axonopathy.

In a preferred embodiment, the present invention is directed to asynergistic combination of suitable cannabinoid, terpene and an alkaloidsuch as atropine. In this embodiment, such combination can be in a watersoluble solution, suspension, or other suitable delivery system, or in akit. In another embodiment, any such ingredients may be linked togetherby way of a biodegradable linker system releasing individual activeingredients.

In another embodiment, the present invention provides a synergisticcombination of a CB receptor agonist, or partial agonist with asecondary pain medication including but not limited to opioids, NSAIDS,gabapentin, pregabalin, a benzodiazepine, atropine, oxime, antioxidants(e.g., grape seed, blueberry extracts, vitamin E, and vitamin C), andsuitable alkalizing agents.

The present invention discloses the novel uses of cannabinoid receptormodifiers in the treatment of the symptoms associated with the OPexposure. By way of example, cannabinoid receptor agonists employed inthe present invention include, but are not limited to, delta 9THC, CBD,CBN, nabilone, dronabinol, nabiximols, or mixtures thereof. Cannabinoidreceptor antagonists include rimonabant.

In another aspect of the present invention, endogenous ligands of thecannabinoid receptors, such as anandamide and 2-AG, and endocannabinoidmetabolizers diacylglycerol lipase (DAGL) and degradation of these lipidmediators (fatty acid amide hydrolase (FAAH) and MAGL (monoacylglycerollipase)) are formulated in combination with cannabinoid receptormodifiers such as 9THC, CBD, CBD-V, THC-V, CBN, nabilone, dronabinol,nabiximols, and rimonabant. In a more preferred embodiment, thecombination comprises at least any two of 2-AG, DAGL, 9THC, CBD, CBN,nabilone, dronabinol, Epidiolex®, nabiximols, and rimonabant. Otherminor lipid metabolites different from, but chemically similar to,anandamide and 2-AG are also suitable for the presently describedformulations.

In at least another embodiment, the invention manipulates theendocannabinoid system, a G-protein-coupled cannabinoid receptor totreat symptoms associated with the OP toxicity. In the brain,endocannabinoid primarily influences neuronal synaptic communication andaffects biological functions, including eating, anxiety, learning andmemory, reproduction, metabolism, growth and development, via an arrayof actions throughout the nervous system. In at least one aspect of thepresent invention, EC signaling function is targeted to improve thetherapeutic benefits of cannabinoids and terpenes in protecting subjectsat risk due to carbamate or OP exposure. In another aspect of thepresent invention, the agonists used to activate or selectively blockone type of cannabinoid receptor more potently than the other typepartial agonists or full agonists with differing CB1 and CB2 receptoraffinities.

In another aspect, the present invention is the new discovery of thecorrelation of desirable properties of CB agonists and supplementalterpenes in alleviating the symptoms of toxic OP or carbamate exposure.In a preferred embodiment, such properties include pupillary dilatationor at least a decrease in miosis and recovery to normal size, dry eyes,dry mouth, muscle relaxation, neuroprotection against oxidative stress,and anxiolysis. In other word, those of ordinary skill in the art wouldappreciate that the undesirable properties of recreationally smokingmarijuana causes, i.e., dry eyes, dilated pupils, dry mouth, reducedability to vomit if one desires to vomit, and difficulty withmicturition are shown herein to be serendipitous benefits, desirablyprevent, decrease or provide therapeutic effects in the context of OPand carbamate toxicity. Those of ordinary skill in the art can furtherappreciate that the ideal property sought in cananbinoid therapy isdevoid of unwanted psychoactive components, or attempts to minimize themin a risk: benefit assessment, except for perhaps an anxiolytic effectand reduction in memory of being acutely sick from OP or carbamateintoxication.

It is also well established that CB 1 receptors are widespread in thebrain which can explain its involvement in multiple memory stages thatmight require different neural substrates. In this context, severalintriguing reports suggest the presence of CB 1 receptors in astrocytes.See Navarrete M., Araque A. 2010. Endocannabinoids potentiate synaptictransmission through stimulation of astrocytes. See Neuron 68, 113-126)and mitochondria (Benard G., et al. 2012. Mitochondrial CB 1 receptorsregulate neuronal energy metabolism. Nat. Neurosci. 15, 558-56), wherethey can also participate in the control of cognitive processes.

In the brain, cannabinoids and endocannabinoids modulate a number ofintracellular signaling pathways, some critically involved in thedeleterious effect of cannabinoids on learning and memory processes. Theinvolvement of the mammalian target of the rapamycin pathway andextracellular signal-regulated kinases, together with their consequentregulation of cellular processes such as protein translation, seem toplay a critical role in the amnesic-like effect of cannabinoids. In atleast one embodiment, methods of limiting brain toxicity and cognitiveimpairment associated with OP exposure are disclosed. In such methods,cannabinoids are directly and locally administered to brain regionsidentified to be at risk secondary to OP toxicity. Mode ofadministration in this aspect of the invention includes suitablydesigned nasal and/or regional catheters.

In at least one embodiment of the present invention, CB agonists can beadministered locally, that is cutaneously, over areas of skin sweatingand fasiculations and directly to the site(s) of interest such as vianasal applicators to the sphenopalatine ganglion and cribiform plate orby way of inhalation for rapid absorption. In another embodiment, the CBagonists are administered ophthalmically and buccally in the form of anisotonic solution, extracts, ointments, inhaler or injectable. Inanother embodiment, a water soluble delivery system is administered byinhalation via an electric charge e-cigarette or a nebulizer.

In a preferred embodiment, the formulation contains a sufficient amountof cannabinoid to competitively inhibit the binding of OP to the AChE.In at least one embodiment the formulation contains 27 mg of 9THC and atleast 25 mg of CBD, COG or CADGE in alkyl alcohol. Ina more preferredembodiment, the formulation comprises 1-3 mg of (−)-delta-9THC and 25 mgCBD, wherein each 100 microliter spray for sublingual delivery containsup to 0.05 g alcohol.

In another embodiment, at least a composition containing a terpenemixture is described. In such embodiment, terpenes may be a combinationof limonene: pinene: myrcene: linalool:

beta caryophylene: terpineol: terpinolene in such ratios as 1-10: 1-10:1-6: 1-6: 0.25-3: 0-10: 0-10, respectively. In another embodiment, theratio between such terpenes is 4:4:3:3:1:0:0. In yet another embodiment,the ratio between such terpenes is respectively 4:7:3:3:2:0:0.

In another embodiment, other ingredients can be used to formulate astable cannabinoid, terpene, and alkaloid composition. Such ingredientsinclude but are not limited to Sterile Water, Organic VegetableGlycerine, phospholipids, glycerols, polyethylene glycerol, or volatileacid to formulate a Cannabis extract having a concentration of 15-50 mgof cannabinoids per ml, and 5% alcohol (for preservation). In anotheraspect of the invention, the cannabinoids may be present and mixed withGrapeseed Oil with an organic solvent such as alcohol ranging from 0-5%w/v.

In a more preferred embodiment such formulation can be applied for amaximum of 25 sprays per day with at least a 15-minute gap betweensprays. In another embodiment, such formulation is applied for a totalof 15 sprays per week.

In another embodiment, the CB agonist is administered orally. At leastone suitable drug is nabilone, a synthetic cannabinoid. Nabilone occursas a white to off-white polymorphic crystalline powder. In aqueousmedia, the solubility of nabilone is less than 0.5 mg/L, with pH valuesranging from 1.2 to 7.0. Chemically, nabilone(±)-trans-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethylis similar to the active ingredient found in naturally occurring 9THC.In at least one embodiment, nabilone can be administered orally at dosesranging from 0.005 mg to 200 mg, preferably 1 mg to 100 mg in a tablet,capsule, oral solution, immediate or extended release formulations. In amore preferred embodiment nabilone is administered orally at 0.05, 0.5,1, or 2 mg and two to three times a day.

In another aspect of the present invention, those of ordinary skill inthe art would appreciate that the present invention establishes the linkbetween antagonizing specific and general manifestation activities ofthe chemical war nerve agents of the G and V classes as well as toxicitysecondary to OP or carbamate insecticide exposure in humans. In at leastone embodiment, the formulation containing the CB agonist or modulatoris administered in the form of an eye drop or ointment. In this aspectof the invention, the eye drop may be used to prevent or minimize miosisand/or ciliary muscle spasm and/or lacrimation secondary to G and Vagent or carbamate exposure.

In another aspect of the invention, the CB receptor agonist can be anactive metabolite of THC. In another embodiment, the CB agonist ormodifier can be administered intranasally to the sphenopalatine ganglionand cribiform plate regions of the patient with or without atropine,with or without a decongestant, or with or without a local anesthetic.In a more preferred embodiment, this mode of administration isaccomplished by a long-acting local anesthetic ingredient. As usedherein, the CB modifiers include such compounds that can compete withendocannabinoids or can enhance agonistic activities at such receptorsites.

In another aspect of the invention, the CB receptor agonist isadministered via inhalation to mucosal membranes and alveoli of therespiratory tract via the mouth or nose. In this aspect of theinvention, the agonist may also be administered via vaporization, or anebulization via a mask nebulizer, below the temperature of combustionso as to be less irritating to mucosal and alveoli of the respiratorytract via the mouth or nose. In another embodiment, the cannabinoid maybe delivered to the alveoli as well as to the sphenopalatine ganglion,olfactory nerve, and cribiform plate.

In yet another embodiment, the cannabinoid formulation is administeredby inhalation, via nose and/or via mouth in the form of a nanomolarformulation or a liposomal formulation that includes added terpenesand/or atropine dry powder via suitable metered dose inhaler, or anelectronic nebulizer, designed to deliver therapeutically effectiveamount of the agonist to the lung. In a more preferred embodiment, theCB receptor agonist is in dry powders or liposomes having particles sizediameters ranging from 10 nanometers to 3000 nm, preferably ranging from50 nm to 2000 nm. In a more preferred embodiment, the liposomes have awall containing phosphatidylcholine, phosphatidic acid, cholesterol andphosphatidylethanolamine.

In another aspect of the invention, the CB receptor agonist is preparedin the form of a culinary extract in the form of or resembling butter ormargarine to be used for baking and cooking. In another embodiment, theproduct is in a form ready for vaporization such as in an E cigarette,or administration into a gas mask, bag/valve mask or CPAP device, or anyform combining cannabinoids with or without added terpenes, butoptionally with atropine, an oxime and/or a benzodiazepine forcombination therapy. In a preferred embodiment, the potentanticholinergic drug combination includes a cannabinoid modulator withor without terpenes in combination with atropine, oxime and abenzodiazepine.

In certain embodiments of the present invention a composition containingthe CB agonist or a modifier can further contain apharmaceutically-acceptable carrier component. Without limitation, sucha composition can comprise a racemic mixture of compounds.

In another embodiment, the invention relates to a method for use intreating or preventing ophthalmic pain, muscular spasticity,neuromuscular pain, including neuropathic pain secondary to OP orcarbamate toxicity. In a more preferred embodiment, the preferredcombination product is used as an adjunctive therapy to standard OP orcarbamate toxicity medical management.

In at least one aspect of the invention, the inventor disclosesformulations containing cannabinoid that are used to alleviate orprevent brain injuries that can be caused by prolonged OP or carbamateexposure causing increased cholinergic tone. It has been shown thatwithin the hippocampus at least, cannabinoids presynaptically inhibitthe release of acetylcholine, possibly through the activation of CB 1receptors located on cholinergic nerve terminals. Direct in vivomicrodialysis studies in rats also showed cannabinoid-induced decreasesin acetylcholine release in the hippocampus through a CB 1receptor-mediated mechanism. In at least one aspect of the presentinvention, the cannabinoid compositions are used forPrevention/treatment/mitigation of OP or carbamate induced braininjuries.

In this aspect of the invention, the pharmaceutical composition is inoral, nasal, topical, ophthalmic, buccal, sublingual, rectal, vaginal,vapor, and/or parenteral form.

The above active compounds may also be used as part of an in vitroassay, for example, in order to determine whether a candidate host islikely to benefit from treatment with the compound in question. Anyactive compound of the present invention may also be used as a standard,for example, in an assay, in order to identify other active compounds,other anti-proliferative agents, other anti-inflammatory agents, etc.

In yet another aspect of the instant invention, the IC50 or the halfmaximal inhibitory concentration of the candidate compounds weredetermined to assess drug potency and potential dosing regimens for invivo use. One of ordinary skill in the art is readily able to ascertainsuch information using commonly known methodologies. As it has been welldescribed in the art, IC50 represents and measures how much of aparticular substance/molecule is needed to inhibit some biologicalprocess by 50%. In the instant case, the IC50 of the candidate compoundswere determined as the concentration that led to a response of 50%compared to the vehicle control cells.

As noted herein, the salts of the compounds of this invention refer tonon-toxic “pharmaceutically acceptable salts.” Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their pharmaceutically acceptable salts. When the compounds of thepresent invention contain a basic group, salts encompassed within theterm “pharmaceutically acceptable salts” refer to non-toxic salts whichare generally prepared by reacting the free base with a suitable organicor inorganic acid. Representative salts include any such salt known inthe art. Where compounds of the present invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts.

To treat a human patient, an effective amount of one or more compoundsof the present invention, or a pharmaceutically-acceptable salt thereof,is administered to the human subject in need so as to promote exposureto or contact of the tissue at risk or the targeted region of the bodyor nerves, synapses, or neuromuscular junctions, or organ systemsincluding but not limited to the autonomic and central nervous systems.Effective dosage forms, modes of administration and dosage amounts maybe determined empirically, and making such determinations is within theskill of the art.

It is understood by the physician, pharmacists or clinician of ordinaryskill in the art that the dosage amount will vary with the activity ofthe particular compound employed, course and/or progression of thedisease state, the route of administration, the rate of excretion of thecompound, status of the nervous system, renal and hepatic function ofthe patient, the duration of the treatment, the identity of any otherdrugs being administered to the subject, age, weight and like factors.

As discussed herein, the cannabinoid compounds of the present inventioncan be administered in such oral dosage forms as tablets, capsules (eachof which includes sustained release or timed release formulations),pills, powders, micronized compositions, granules, elixirs, tinctures,suspensions, ointments, vapors, liposomal particles, nanoparticles,syrups and emulsions. Likewise, they may also be administered inintravenous (bolus or infusion), intraperitoneal, topical (e.g., dermalepidermal, transdermal, ophthalmically such as ocular eyedrop,intranasally, subcutaneous, inhalation, intramuscular or transdermal(e.g., patch) form, all using forms well known to those of ordinaryskill in the pharmaceutical arts. Again, the ordinarily skilledphysician, veterinarian or clinician or a clinical pharmacist mayreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Dosages of phytocannabinoids, e.g., THC and CBD, or synthetics of thepresent invention, when used for the indicated effects, will rangebetween about 0.0001 mg per kg of body weight per day (mg/kg/day) toabout 100 mg/kg/day, preferably 0.001 to 20 mg/kg/day, and mostpreferably 0.01 to 10.0 mg/kg/day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. A medicament typically containsfrom about 0.01 mg to about 500 mg of the active ingredient, preferably,from about 1 mg to about 100 mg of active ingredient. Intravenously orvia a vapor inhalation, the most preferred doses will range from about0.01 to about 10 mg/kg/minute during a constant rate infusion or rate ofrespiration. Compounds of the present invention may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three or four or six times daily. In the case of aprodrug construct, those of ordinary skill in the art would appreciatethat the clinical outcome follows the same serum concentrations orclinical endpoints as those of THC or CBD.

In at least one embodiment, the method of treatment includes bothprophylactic and active treatment regimens. In at least one suchembodiment, the suitable composition contains a blend of CBD to THChaving the ratio of CBD: THC in ranges of 10-400 mg: 0.0001-10 mg. Inyet another embodiment, such method includes the step of administering ablend of terpenes optionally including pinene. In a more preferredembodiment, pinene may be added in case there is exposure to oxime. Thisis because pinene has a beneficial bronchodilatorory effects tocounteract OP or carbamate induced bronchospasm. However, pinene alsohas an anticholinesterase property. This property would make pinene moreideal as a prophylactic and less ideal as a post-exposure therapeuticunless an oxime and atropine are administered shortly after OP or toxiccarbamate exposure. THC also has an anticholinesterase property thatmakes it useful for prophylaxis only in microgram quantities. THC islikewise less ideal as a post-exposure therapeutic in other thanmicrogram quantities unless an oxime and atropine are administeredshortly after OP or toxic carbamate exposure

In another embodiment, the method is intended for active treatment ofemotional and neurophysiological stresses, involuntary eye musclestwitches, bronchospasm, fasiculations, tremors, seizures, headaches,neuropathy and neuropsychiatric disorders including PTSD. In yet anotherembodiment, prophylactic methods are contemplated to counter OPtoxicity. Accordingly, such methods include the step of sniffing aterpene mixture, wherein the terprene mixture contains a terpene blendof limonene, myrcene, linalool, beta caryophylene, terpineol,terpinolene optional pinene, and mixtures thereof.

As noted herein, the compounds of the present invention may be used incombination with other pain management, anticholinergic agents or otheragents which will enhance the treatment regime for the human subjects.The individual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms to patients orregions of such patients in need of such therapy. The instant inventionis therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulto treat the targeted cancer condition includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to optimal cholinergic and general nervous systemfunctioning.

Pharmaceutical formulations of the present invention include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal and/or parenteral administration. Regardless of theroute of administration selected, the active ingredient(s) areformulated into herbal and pharmaceutically-acceptable dosage forms byconventional methods known to those of skill in the art.

The amount of the active ingredient(s) which will be combined with acarrier material to produce a single dosage form will vary dependingupon the host being treated, the particular mode of administration andall of the other factors described above. The amount of the activeingredient(s) which will be combined with a carrier material to producea single dosage form will generally be that amount of the activeingredient(s) which is the lowest dose effective to produce atherapeutic effect.

In another aspect of the invention, a cannabinoid formulation isdescribed to prevent unauthorized diversion of a formulation thatcontains clinically significant amounts of THC or other CB1 agonist withpsychoactive properties. As such the formulation agonist withpsychoactive activity may have atropine or a similar anticholinergicagent added. The anticholinergic property of atropine, in the absence ofOP or carbamate, will cause an uncomfortably dry mouth and dryness atother mucous membranes. Approved medications that contain atropine (orpharmacologically similar belladonna alkaloids) to prevent diversion ofa narcotic or barbiturate, respectively, and/or to aid in intendedtherapeutic activity include for diarrhea diphenoxylate/atropine and forspastic colon, phenobarbital with hyoscyamine, atropine and scopolamine.Spastic colon is also called IBS, or Irritable Bowel Syndrome. IBS is asymptom-based diagnosis characterized by chronic abnormal pain,discomfort, bloating, and alteration of bowel habits. As a functional GIdisorder, IBS has no known organic causes diarrhea or constipation maypredominate, or they may alternate (classified as IBS-D, IBS-C or IBS-A,respectively).

Another aspect of the present invention provides compounds having thefollowing structure:

In such embodiment, L is a linker bridging a cannabinoid moiety to analkaloid moiety.

In a preferred embodiment, L is

attached at the designated points, Z═O, S, or NR7, and where R7 =H,alkyl, aryl, —OH, or —O—C1-C3 alkyl.

In a more preferred embodiment, A is aryl, heteroaryl, fused pyran, orfused tetrahydropyran; B is C(═O)—O—R6, where R6 is an azabicyclo ringsubstituent (alkaloid); and C is H, F, or C1-C3 alkoxy, CN, orS(O)_(n)CH₃, where n=0-2, and Z═O. Methods of preparing such compoundsgenerally follow the conventional methods known in the art.

In at least one embodiment, Z is O (a carboxy group linker), and the newcompound has the formula:

Methods of preparing compounds are understood in the art and followthose employing carboxylate, phosphate and amine moieties. Methods ofpreparing formulations or compositions include the step of bringing theactive ingredient(s) into association with the carrier and, optionally,one or more accessory and/or stabilizing or preserving ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing the active ingredient(s) into association with liquid carriers,or finely divided solid carriers, or both, and then, if necessary,shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or nonaqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup or tincture, or as pastilles (using an inert base, suchas gelatin and glycerin, or sucrose and acacia) and/or as mouth washesand the like, each containing a predetermined amount of the activeingredient(s). The active ingredient(s) may also be administered as abolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theprodrug(s), active ingredient(s) (in their micronized form) is/are mixedwith one or more pharmaceutically-acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethyl-cellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the pharmaceuticalcompositions may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugars, aswell as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared using abinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered activeingredient(s) moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient(s) thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres or nanoparticles. They may be sterilizedby, for example, filtration through a bacteria-retaining filter. Thesecompositions may also optionally contain opacifying agents and may be ofa composition that they release the active ingredient(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeingredient(s) can also be in microencapsulated form.

Liquid dosage forms for oral administration of the active ingredient(s)include pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient(s), the liquid dosage forms may contain inert diluentscommonly used in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl acetate, butyl alcohol, benzyl benzoate, propyleneglycol, glycol, oils (in particular, cottonseed, groundnut, corn, germ,olive, castor, hempseed, cocoanut, and sesame oils), terpenes orterpinoids, glycerol or glycerol, amyl alcohol, tetrahydrofurylpolyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents the oral compositions may also include wettingagents, emulsifying and suspending agents, sweetening, flavoring,coloring, perfuming and preservative agents. Suspensions, in addition tothe active ingredient(s), may contain suspending agents as, for example,ethoxylated alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing the active ingredient(s) with one ormore suitable nonirritating excipients or carriers comprising, forexample, cocoa butter, polyethylene glycol, wax or salicylate which issolid at room temperature, but liquid at body temperature and,therefore, will melt in the rectum or vaginal cavity and release theactive ingredient(s). Formulations of the present invention which aresuitable for vaginal administration also include pessaries, tampons,creams, gels, pastes, foams or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for the topical, ophthalmic or transdermal administrationof the active ingredient(s) include powders sprays, ointments, pastes,creams, lotions, gels, solutions, patches and inhalants. The activeingredient(s) may be mixed under sterile conditions withpharmaceutically-acceptable carrier, and with any buffers, orpropellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to theactive ingredient(s), excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, terpenes or terpinoids, or mixtures thereof. Powders and sprayscan contain, in addition to the active ingredient(s), excipients such aslactose, talc, silicic acid, aluminum hydroxide, calcium silicates andpolyamide powder, or mixtures of these substances. Sprays canadditionally contain customary propellants such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compounds of the present invention may be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in the art. A transdermal delivery systemprovides for continuous administration throughout the dosage regimen.Transdermal patches have the added advantage of providing controlleddelivery of the active ingredient(s) to the body. Such dosage forms canbe made by dissolving, dispersing or otherwise incorporating the activeingredient(s) in a proper medium, such as an elastomeric matrixmaterial. Absorption enhancers, such as iontophoresis, can also be usedto increase the flux of the active ingredient(s) across the skin or amucous membrane or a mucocutaneous junction area. The rate of such fluxcan be controlled by either providing a rate-controlling membrane ordispersing the active ingredient(s) in a polymer matrix or gel.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamines or phosphatidylcholines.

Another mode of delivery for the compounds of the present invention maybe delivery via the use of monoclonal antibodies as individual carriersto which the compound molecules are coupled. The compounds of thepresent invention may also be coupled with soluble polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidone, yeast derivatives (e.g., glucans), pyrancopolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydro gels.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise the active ingredient(s) in combination with oneor more pharmaceutically-acceptable sterile isotonic aqueous ornonaqueous solutions, suspensions or emulsions, or sterile powders whichmay be reconstituted into sterile injectable solutions or dispersionsjust prior to use, which may contain antioxidants, buffers, soluteswhich render the formulation isotonic with the blood of the intendedrecipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the formulation. In some cases, in order to prolong theeffect of the active ingredient(s), it is desirable to slow theabsorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the active ingredient(s) then depends upon its/theirrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption ofparenterally-administered active ingredient(s) is accomplished bydissolving or suspending the active ingredient(s) in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe active ingredient(s) in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of the activeingredient(s) to polymer, and the nature of the particular polymeremployed, the rate of release of the active ingredient(s) can becontrolled. Examples of other biodegradable polymers includepoly(orthoesters) and poly(anhydrides). Depot injectable formulationsare also prepared by entrapping the active ingredient(s) in liposomes ormicroemulsion or nanoparticles which are compatible with body tissue.The injectable materials can be sterilized for example, by filtrationthrough a bacterial-retaining filter.

The formulations may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, or in specialized capsulesfor vapor or nebulized administration and may be stored in a lyophilizedcondition requiring only the addition of the sterile liquid carrier, forexample water or oil for injection, immediately prior to use.Extemporaneous injection solutions and suspensions maybe prepared fromsterile powders, granules and tablets of the type described above.

Unless otherwise specified all starting materials and reagents are ofstandard commercial or medicinal grade, and are used without furtherpurification, or are readily prepared from such materials by routinemethods. Those skilled in the art of clinical therapeutics willrecognize that starting materials and reaction conditions may be variedto achieve the desired end product. In at least one embodiment, a kit isdescribed containing differing prophylactic and active treatment regimenfor a cannabinoid rescue regimen.

In this aspect of the invention, the cannabinoid therapy may include aterpene blend containing limonene, alpha pinene, myrcene, linalool andbeta carylophylene preferably in weight ratios of about 4:7:3:3:2. (SeeFIG. 1). In another embodiment such prophylactic kit contains CBDcontaining compositions for both inhalation therapy and oraladministration. In another embodiment, the therapy or the terpene blendmay contain THC in amounts less than 1 mg.

In another aspect of the invention, the cannabinoid rescue regimen is akit for active treatment. In addition to the terpene blend and CBDcomposition, the active treatment kit contains THC: CBD containingcompositions in the ratios of 1:10, 1:12.5, 1:15, 1:20, and 1:40 w/w.Such kit may further contain hemp oil, atropine, an oxime, abenzodiazepine, instructions as to the order of treatment and otheradministration means. In a more preferred embodiment, the THC: CBDcomposition and terpenes are water soluble. In another preferredembodiment, the atropine/oxime is lipid soluble.

The following examples are meant to better define the scope of thepresent invention.

EXAMPLE 1

OP toxicity was determined using DFP toxicity. Male and female albinorats (total 4 rats) were singly dosed subcutaneously with differentamounts of the DFP. Severity of salivation, lacrimation, urination anddefecation (SLUD) signs were measured at dose levels of 0.63, 1.88,1.25, and 2.5 DFP mg/kg. Dose escalation is used if the previous dosesused do not, induce sufficient responses to test efficacy of the testarticle such as abnormal pupil response, SLUD, arousal, abnormal motormovement, gait and posture.

EXAMPLE 2

The same protocol as in Example 1 is conducted in a primate to measurethe OP DFP toxicity by monitoring the same parameters to find a doselevel that would provide clear and measureable evidence of DFP toxicityin a primate.

EXAMPLE 3

In order to test the onset of cannabinoid and terpene activities inrats, a combination of THC, CBD, and terpenes were administered to theanimals. In accordance with an IRB approved protocol, a first group ofrats were administered a terpene blend for 20 seconds of sniffing of theblend. After sniffing of the terpene blend, different combinations ofcannabinoids by themselves or in cannabinoid/terpene blends wereadministered by oral gavage.

At least one of the blend combinations was composed of D-limonene: alphapinene: myrcene, linalool: beta caryophylene in volumetric ratios ofabout 4:4:3:3:1 respectively to make approximately a 30 mg/kg dose. Thesame method may be used to explore other combinations within the scopeof the ratios described herein above, such as for example, a terpeneblend containing limonene, alpha pinene, myrcene, linalool and betacarylophylene preferably in weight ratios of about 4:7:3:3:2 asdescribed in FIG. 1.

In another experiment the animals are given THC at doses of 0.001, 0.01,0.05, 0.1, 0.5, 1, and high doses of 2.5 or 3 mg/kg. Another group ofthe animals are given a mixture containing CBD:THC at CBD dosesincluding but not limited to 0.1, 1, 10, 12.5, 15, 20, 25, 30, 37.5mg/kg and such THC doses to make up ratios of 10:1, 12.5:1, or 15:1,20:1, 25: 1, 40:1, 100:1, and 200:1 CBD:THC respectively.

In another experiment the animals are given CBD at doses of 0.25, 1, 5,50, 75, 100, 150, and 200 mg/kg and a terpene blend at a dose of 40mg/kg-120 mg/kg.

In another experiment the animals are given THC at 2.5 mg/kg, CBD at 15mg/kg and terpene blend at 40 mg/kg. In another experiment the animalsare given an undiluted terpene blend via sniffing for 2 seconds. Thenthe THC/CBD/terpene blend was administered by oral gavage 2.25 hoursprior to subcutaneous administration of DFP.

Observations: Female rats tolerate higher doses of DFP than male rats.Cannabinoid effects such as hyperthermia, abnormal gait and posture seenwith both THC and CBD receiving animals, particularly more prominent at8 hours than at 4 hours after dosing, showing splayed hind limbs andhunched or crouched body position. Both DFP and cannabinoids causesignificant hypothermia in rats, (but not in primates). All animalsreceiving cannabinoids with and without additional terpenes or just aterpene blend recovered at 24 hours after receiving the test materials.Terpenes by themselves appeared very well tolerated, except the rats didnot like the smell of linalool. The degree of hypothermia observed withgroups receiving CBD was unexpected, potentially due to questionableintegrity of CBD formulation. CBD is expected to attenuate hypothermiaassociated with THC in rats.

EXAMPLE 4

Animals were tested for efficacy of the cannabinoid rescue therapy. Inthe first study, 4 male and 4 female Sprauge Dawley rat pups weretreated initially with DFP subcutaneously at dose of 1.35 mg/kg formales and 1.9 mg/kg for females. A Cannabinoid mixture was delivered byoral gavage at 2.25 hours prior to the administration of DFP and again24 hours later. Animals could then sniff terpene blend for 2 secondsimmediately prior to gavage and again the terpene alpha pinene for 2seconds prior to first DFP subcutaneous injection. Similar approach maybe taken in other species, however, cannabinoids and terpenes may beadministered as vapors or in ways other than oral gavage.

An outcome of at least 10%, improvement in toxicity parameters is to beobserved in animals, such as primates who received THC, CBD and terpenesprophylactically. Small doses of atropine/oxime will be available assoon as possible after exposure vs. conventional therapy of onlyatropine/oxime. These improvement changes are less likely to be seen inrodents due to biological differences in reactions to cannabinoids.Related parameters in other systems would indicate at least a 10%overall improvement in all other major organ systems impacted by DFP oranother OP.

For example, animals receiving the treatment regimen would show at leasta 10% less abnormal respiratory rate, hypoxemia, audible wheeze, digitalpulse oximetry abnormalities, abnormalities in FEV1 (forced expiratoryvolume) at one (1) second and vital capacity as well as any flow volumeloop measurable by spirometry. In the alternative, respiratory distressassessments based on pulse oximetry and/or arterial blood gas analysisincluding CO2 retention as compared to non-treatment group. Similarly,animals receiving the cannabinoid rescue regimen will exhibitsubstantial clinical response to supplemental oxygen in part due toreduced bronchospasm and respiratory hyper secretion (bronchorhinorhea).

Neuropsychiatric exam will also show at least 10% less disorientationand learning abnormalities or measures of cognitive function at 30 daysafter moderate to severe OP exposure (following at least a 3-day washoutfrom any significant dose of THC or a CB 1 receptor agonist). Similarresults would be observed for parameters indicative of axonopathy fromdelayed OP-induced neuropathy. Other clinical signs related to theseverity of PTSD, severity of anxiety, depression are to be monitored inappropriate interval respectively associated with development ofabnormal signs in the animal models. Those of ordinary skill in the artcan appreciate that a proper approach would implement a washout periodafter psychoactive cannabinoid administration before any memoryassessments or cognitive task assessments could be determined.

Neuromuscular exam will also provide for at least a 10% decrease inseverity of tremors, other abnormal movements, and a 20% decrease inseizures. In a preferred outcome, at least a 20% decrease in LD 50studies is observed in primates in groups that have receivedprophylactically alpha pinene and low dose THC and CBD whereconcentrations of CBD to THC follows at least a 20:1 ratio respectively.

In an alternative regimen, the treatment plans include (a) CBD with orwithout a terpene blend and optionally (b) atropine or oxime or bothfollowing OP exposure.

At least one aspect of the present invention describes improvements thatwould include at least 10% improvements in hypersalivation and eye pain,clinically significant SLUD, dryness and other cholinergic adverseeffects as compared with a prophylactic pyridostigmine bromidetreatment. It is contemplated that in primates cannabinoid therapyresults in a more rapid return of pupil size from the miosis induced byan OP or a carbamate. OP-induced miosis from G class nerve agent vaporsthat reach the eye is resistant to treatment with atropine.

In another observation, neuroprotective effect from cannabinoids as anadjunct to standard therapy will be superior to standard therapy alone30 days after exposure and when assessed against a standalonepyridostigmine treatment.

In yet another embodiment, high CBD:THC (>20:1) ratios, with or withoutterpenes but if with terpenes then without significant pinene wouldprovide an alternative standard treatment in cases where atropine and anoxime will not be administered in a timely fashion. This approach may besuitable particularly for civilian use.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as claimed in the appending claims.

All publications, patents, and patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated herein byreference.

I claim:
 1. A compound having the following structure:

wherein L is selected from the group consisting of

Z═O, S or NR7, R7=H, aryl, —OH, —O, or lower alkoxy; A is aryl,heteroaryl, fused pyran or a fused tetrahydropyran; B is C(═O)—O—R6; R6is an alkaloid azabicyclo ring substituen; C is H, F, lower alkoxy, CN,S(O)_(n)CH₃ where n=0-2, and Z═O.
 2. The compound of claim 1, selectedfrom the group consisting of: